Inflammation
Inflammation is a response of vascularized tissues to infection or injury and is affected by adhesion of leukocytes to the endothelial cells of blood vessels and their infiltration into the surrounding tissues. In normal inflammation, infiltrating leukocytes release toxic mediators to kill invading organisms, phagocytize debris and dead cells, and play a role in tissue repair and the immune response. However, in pathologic inflammation, infiltrating leukocytes are over-responsive and can cause serious or fatal damage. See, e.g., Hickey, Psychoneuroimmunology II (Academic Press 1990).
The integrins are a family of cell-surface glycoproteins involved in cell-adhesion, immune cell migration and activation. Alpha-4 (α4) integrin is expressed by all circulating leukocytes except neutrophils, and forms heterodimeric receptors in conjunction with either the beta1 (β1) or beta7 (β7) integrin subunits. Both alpha-4 beta-1 (α4β1) and alpha-4 beta-7 (α4β7) play a role in the migration of leukocytes across the vascular endothelium (Springer et al., Cell, 1994 76: 301-14; Butcher et al., Science, 1996, 272: 60-6) and contribute to cell activation and survival within the parenchyma (Damle et al., J. Immunol., 1993; 151: 2368-79; Koopman et al., J. Immunol., 1994, 152: 3760-7; Leussink et al., Acta Neuropathol., 2002, 103: 131-136). α4β1 is constitutively expressed on lymphocytes, monocytes, macrophages, mast cells, basophils and eosinophils.
α4β1 (also known as very late antigen-4, VLA-4), binds to vascular cell adhesion molecule-1 (VCAM-1) (Lobb et al., J. Clin. Invest., 1994, 94: 1722-8), which is expressed by the vascular endothelium at many sites of chronic inflammation (Bevilacqua et al., 1993 Annu. Rev. Immunol., 11: 767-804; Postigo et al., 1993 Res. Immunol., 144: 723-35). α4β1 has other ligands, including fibronectin and other extracellular matrix (ECM) components.
Intercellular adhesion mediated by α4β1 and other cell surface receptors is associated with a number of inflammatory responses. At the site of an injury or other inflammatory stimulus, activated vascular endothelial cells express molecules that are adhesive for leukocytes. The mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release chemical mediators to combat infection.
Rheumatoid Arthritis
Rheumatoid arthritis (“RA”) is a chronic inflammatory disease that causes pain, swelling, stiffness, and loss of function, primarily the joints. RA is estimated to affect approximately 1 percent of the world's population. In the U.S. alone, an estimated 2.1 million people suffer from the disease. This relatively high frequency suggests a complex etiology and pathogenesis.
The disease process leading to RA begins in the synovium, the membrane that surrounds a joint creating a protective sac. In healthy individuals, the synovium produces synovial fluid that lubricates, nourishes and protects joint tissues. This clear fluid lubricates and nourishes the cartilage and bones inside the joint capsule. In individuals suffering from RA, the immune system, for unknown reasons, attacks the cells inside synovium. Leukocytes infiltrate from the circulation into the synovium causing continuous abnormal inflammation (i.e., synovitis). Consequently, the synovium becomes inflamed, causing warmth, redness, swelling, and pain. The collagen in the cartilage is gradually destroyed, narrowing the joint space and eventually damaging bone. The inflammation causes erosive bone damage in the affected area. During this process, the cells of the synovium grow and divide abnormally, making the normally thin synovium thick and resulting in a joint that is swollen and puffy to the touch. See, e.g., Paul, Immunology (3d ed., Raven Press, 1993).
It is believed that bone damage begins during the first year or two that a person has the disease. This is one reason why early diagnosis and treatment are important in the management of RA. As the disease progresses, abnormal synovial cells begin to invade and destroy the cartilage and bone within the joint. The surrounding muscles, ligaments, and tendons that support and stabilize the joint become weak and unable to work normally. RA also causes more generalized bone loss that may lead to osteoporosis, making bones fragile and more prone to fracture. All of these effects cause the pain, impairment and deformities associated with RA.
Although RA almost always develops in the wrists and knuckes, some patients experience the effects of the disease in places other than the joints. For instance, the knees and the ball of the foot are often affected as well. Often, many joints may be involved, and even the spine can be affected. In about 25% of people with RA, inflammation of small blood vessels can cause rheumatoid nodules, or lumps, under the skin. These are bumps under the skin that often form close to the joints. As the disease progresses, fluid may also accumulate, particularly in the ankles. Many patients with RA also develop anemia, or a decrease in the normal number of red blood cells. Other less prevalent effects include neck pain, dry eyes and dry mouth. On rare occasions, patients may also develop inflammation of the-blood vessels, the lining of the lungs, or the sac enclosing the heart.
RA has several special features that differentiate it from other types of arthritis. For example, RA generally occurs in a symmetrical pattern—if one knee or hand is involved, the other one is also. The disease often affects the wrist joints and the finger joints closest to the hand. RA usually first affects the small joints of the hands and feet, but may also involve the wrists, elbows, ankles and knees. It can also affect other parts of the body besides the joints. In addition, patients with the disease may have fatigue, occasional fever, and a general sense of not feeling well (malaise).
Another distinct feature of RA is the variance between individuals. For some, it lasts only a few months or a year or two and subsides without causing any noticeable damage. Other people have mild or moderate disease, with periods of worsening symptoms (flares) and periods in which they feel better (remissions). In severe cases, the disease is chronically active most of the time, lasting for many years, and leading to serious joint damage and disability.
RA encompasses a number of disease subtypes, such as Felty's syndrome, seronegative RA, “classical” RA, progressive and/or relapsing RA, and RA with vasculitis. Some experts classify the disease into type 1 or type 2. Type 1, the less common form, lasts a few months at most and leaves no permanent disability. Type 2 is chronic and lasts for years, sometimes for life.
RA is believed to be one of several “autoimmune” diseases (“auto” means self), so-called because a person's immune system attacks his or her own body tissues. Although much has been learned about the process leading to RA, researchers have yet to uncover all of the factors that lead to this disease. One prevalent theory is that a combination of factors trigger RA, including an abnormal autoimmune response, genetic susceptibility, environmental, biologic factors, hormonal, and reproductive factors. Nonetheless, despite intensive research, the cause of RA remains obscure. See El-Gabalawy et al., ARTHRITIS RES. 4(suppl 3):S297-S301 (2002).
RA occurs across all races and ethnic groups. Although the disease often begins in middle age and occurs with increased frequency in older people, children and young adults may also develop juvenile RA. Like other forms of arthritis, RA exhibits a clear gender bias: approximatley two to three times as many women as men have the disease (Lawrence et al., Arthritis Rheum., 1998, 41:778-799). However, a genetic predisposition has been identified and, in white populations, localized to a pentapeptide in the HLA-DR1 locus of class II histocompatibility genes. Environmental factors may also play a role. Immunologic changes may be initiated by multiple factors.
Prominent immunologic abnormalities that may be important in pathogenesis include immune complexes found in joint fluid cells and in vasculitis. Plasma cells produce antibodies that contribute to these complexes. Lymphocytes that infiltrate the synovial tissue are primarily T helper cells, which can produce pro-inflammatory cytokines. Increased adhesion molecules contribute to inflammatory cell emigration and retention in the synovial tissue.
The onset is usually insidious, with progressive joint involvement, but may be abrupt, with simultaneous inflammation in multiple joints. Tenderness in nearly all inflamed joints and synovial thickening are common. Initial manifestations may occur in any joint.
Stiffness lasting less than 30 minutes on arising in the morning or after prolonged inactivity is common. Subcutaneous rheumatoid nodules are not usually an early manifestation. Visceral nodules, vasculitis causing leg ulcers or mononeuritis multiplex, pleural or pericardial effusions, lymphadenopathy, Felty's syndrome, Sjögren's syndrome, and episcleritis are other manifestations. As many as 75% of patients improve symptomatically with conservative treatment during the first year of disease. However, less than 10% are eventually severely disabled despite full treatment. The disease greatly affects the lives of most RA patients. Complete bed rest is occasionally indicated for a short period during the most active, painful stage of severe disease. In less severe cases, regular rest should be prescribed.
Nonsteroidal anti-inflammatory drugs may provide important symptomatic relief and may be adequate as simple therapy for mild RA, but they do not appear to alter the long-term course of disease. Salicylates, such as aspirin, may be used for treatment.
Gold compounds usually are given in addition to salicylates or other NSAIDs if the latter do not sufficiently relieve pain or suppress active joint inflammation. In some patients, gold may produce clinical remission and decrease the formation of new bony erosions. Parenteral preparations include gold sodium thiomalate or gold thioglucose. Gold should be discontinued when any of the above manifestations appear. Minor toxic manifestations (e.g., mild pruritus, minor rash) may be eliminated by temporarily withholding gold therapy, then resuming it cautiously about 2 wk after symptoms have subsided. However, if toxic symptoms progress, gold should be withheld and the patient given a corticosteroid. A topical corticosteroid or oral prednisone 15 to 20 mg/day in divided doses is given for mild gold dermatitis; larger doses may be needed for hematologic complications. A gold chelating drug, dimercaprol 2.5 mg/kg IM, may be given up to four to six times/day for the first 2 days and bid for 5 to 7 days after a severe gold reaction.
Hydroxychloroquine can also control symptoms of mild or moderately active RA. Toxic effects usually are mild and include dermatitis, myopathy, and generally reversible corneal opacity. However, irreversible retinal degeneration has been reported. Sulfasalazine may also be used for treatment of RA.
Oral penicillamine may have a benefit similar to gold and may be used in some cases if gold fails or produces toxicity in patients with active RA. Side effects requiring discontinuation are more common than with gold and include marrow suppression, proteinuria, nephrosis, other serious toxic effects (eg, myasthenia gravis, pemphigus, Goodpasture's syndrome, polymyositis, a lupuslike syndrome), rash, and a foul taste.
Steroids are the most effective short-term anti-inflammatory drugs. However, their clinical benefit for RA often diminishes with time. Steroids do not predictably prevent the progression of joint destruction. Furthermore, severe rebound follows the withdrawal of corticosteroids in active disease. Contraindications to steroid use include peptic ulcer, hypertension, untreated infections, diabetes mellitus, and glaucoma.
Immunosuppressive drugs are increasingly used in management of severe, active RA. However, major side effects can occur, including liver disease, pneumonitis, bone marrow suppression, and, after long-term use of azathioprine and malignancy.
Whatever may be the actual cause, there is no cure for RA, and although the disease is not fatal, disease complications and symptoms may persist throughout an individual's lifetime, and may even shorten survival by a few years. Affected joints may become deformed, and the performance of even ordinary tasks may be very difficult or impossible.